The oncogenic roles and clinical implications of YAP/TAZ in breast cancer

Luo, Juan; Zou, Hailin; Guo, Yibo; Tong, Tongyu; Chen, Yun; Xiao, Yunjun; Pan, Yihang; Li, Peng

doi:10.1038/s41416-023-02182-5

Cited by 18 publications

(16 citation statements)

References 149 publications

(270 reference statements)

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“…Notably, nuclear YAP import remains highly responsive to ECM viscoelastic properties, displaying a linear correlation with cell projected area. These findings underscore the pivotal role of cell contractility in mediating nuclear YAP import in response to matrix viscoelastic properties, complementing the well-established essential involvement of YAP in various aspects of breast cancer development (66). While previous studies have emphasized the role of matrix stiffness in the regulation of metastatic breast cancer cells through YAP signalling (67), our study highlights the pivotal role of substrate viscoelasticity in regulating cell mechanotransduction and migration.…”

Section: Discussionsupporting

confidence: 61%

Matrix viscoelasticity controls epithelial cell mechanobiology through dimensionality

Ciccone,

Oliva,

Versaevel

et al. 2024

Preprint

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In recent years, matrix viscoelasticity has emerged as a potent regulator of fundamental cellular processes and has been implicated in promoting cancer progression. Alongside viscoelasticity, additional ECM cues have been shown to influence migration decision-making of cancer cells, and spatial confinement is now considered as a potential regulator of metastasis. However, our understanding of these complex processes predominantly relies on purely elastic hydrogels, and the exact relationship between matrix viscoelasticity and spatial confinement in driving epithelial cell mechanotransduction and migration during cancer progression remains unclear. Here, we systematically investigated the interplay between matrix stiffness, viscoelasticity and spatial confinement by engineering soft (∼0.3 kPa) and stiff (∼3 kPa) polyacrylamide hydrogels with varying degrees of viscous dissipation, mirroring the mechanical properties of healthy and tumoral conditions in breast tissue. We observed that viscoelasticity modulates cell spreading, focal adhesions and YAP nuclear import in opposite directions on soft and stiff substrates. Strikingly, viscoelasticity enhances migration speed and persistence on soft substrates, while impeding them on stiff substrates via actin retrograde flow regulation. Combining soft micropatterning with viscoelastic hydrogels, we also show that spatial confinement restricts cell migration on soft matrices regardless of matrix viscoelasticity and promotes migration on stiff matrices in a viscoelasticity-dependent fashion. Our findings establish substrate viscoelasticity as a key regulator of epithelial cell functions and unravel the role of the matrix dimensionality in this process.SignificanceWhile matrix elasticity has received significant attention, recent findings underscore the importance of its natural dissipative properties and spatial confinement in regulating cellular processes and tumour invasiveness. However, the intricate interplay between viscoelasticity and spatial confinement in orchestrating epithelial cell behaviour during cancer progression remains elusive. Using micropatterned viscoelastic hydrogels to replicate the mechanical properties encountered during breast tumour progression, we unveil that viscoelasticity modulates cell behaviour and mechanotransduction signals differently on soft and stiff substrates. Increased viscoelasticity enhances migration speed and persistence on soft substrates while impeding them on stiff substrates via actin retrograde flow regulation. Furthermore, spatial confinement restricts cell migration on soft matrices regardless of viscoelasticity, while promoting migration on stiff matrices in a viscoelasticity-dependent manner.

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Section: Discussionsupporting

confidence: 61%

Matrix viscoelasticity controls epithelial cell mechanobiology through dimensionality

Ciccone,

Oliva,

Versaevel

et al. 2024

Preprint

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“…For instance, Digitoxin—a cardiac glycoside commonly prescribed for treating congestive heart failure (Arispe et al, 2008), has also been shown to activate YAP for treating YAP-loss-driven lung SCC (Huang et al, 2017). An extension of our study would imply that inhibitors of YAP (Oku et al, 2015; Yong et al, 2021; Zanconato et al, 2016) may aggravate SCC in select SEs, thereby calling for cautions in their therapeutic exploration (see (Luo et al, 2023)).…”

Section: Discussionmentioning

confidence: 98%

Hippo effector, Yorkie, is a Tumor Suppressor in SelectDrosophilaSquamous Epithelia

Bhattacharya,

Kumari,

Banerjee

et al. 2023

Preprint

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Out-of-context gain of nuclear signaling of mammalian YAP/TAZ or Drosophila Yki, the transcription cofactors of the highly conserved Hippo tumor suppressor pathway, is oncogenic. By contrast, in mechanically strained squamous epithelia (SE), YAP/TAZ/Yki displays developmentally programmed nuclear translocation, leading to its constitutive signaling. How organ homeostasis is maintained in constitutively YAP/TAZ/Yki signaling SE is unclear. Here, we show that Yki signaling negatively regulates the cell growth-promoting PI3K/Akt/TOR signaling in the SEs in the tubular organs of Drosophila. Thus, in the adult male accessory gland (MAG), knockdown of Yki signaling upregulates PI3K/Akt/TOR signaling in its SE-lined lumen, inducing cell hypertrophy, culminating in squamous cell carcinoma (SCC). MAG SCC-bearing adults display early mortality due to cancer cachexia, which is reversed by simultaneous knockdown of a secreted factor, ImpL2, a Drosophila homolog of mammalian IGFBP7, without arresting tumor progression per se. By contrast, a knockdown of PI3K/Akt/TOR signaling suppresses MAG SCC, reversing adult mortality. In the SE-lined lumens in other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, too, knockdown of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy and loss of epithelial homeostasis, culminating in their tumor-like transformation. Thus, Yki signaling turns tumor suppressive in the SEs of tubular organs in Drosophila by arresting runaway PI3K/Akt/TOR signaling.

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“…We further revealed that YAP is primarily responsible for TRIM21‐mediated drug sensitivity. YAP has been reported to be associated with chemoresistance in varies types of human cancer, 40 , 41 , 42 but the downstream target genes responsible for this regulation remain to be explored.…”

Section: Discussionmentioning

confidence: 99%

TRIM21 is critical in regulating hepatocellular carcinoma growth and response to therapy by altering the MST1/YAP pathway

Shu,

Zhou,

Lei

et al. 2024

Cancer Science

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Liver cancer is the sixth most common cancer and the third leading cause of cancer‐related death globally. Despite efforts being made in last two decades in cancer diagnosis and treatment, the 5‐year survival rate of liver cancer remains extremely low. TRIM21 participates in cancer metabolism, glycolysis, immunity, chemosensitivity and metastasis by targeting various substrates for ubiquitination. TRIM21 serves as a prognosis marker for human hepatocellular carcinoma (HCC), but the mechanism by which TRIM21 regulates HCC tumorigenesis and progression remains elusive. In this study, we demonstrated that TRIM21 protein levels were elevated in human HCC. Elevated TRIM21 expression was associated with HCC progression and poor survival. Knockdown of TRIM21 in HCC cell lines significantly impaired cell growth and metastasis and enhanced sorafenib‐induced toxicity. Mechanistically, we found that knockdown of TRIM21 resulted in cytosolic translocation and inactivation of YAP. At the molecular level, we further identified that TRIM21 interacted and induced ubiquitination of MST1, which resulted in MST1 degradation and YAP activation. Knockdown of MST1 or overexpression of YAP reversed TRIM21 knockdown‐induced impairment of HCC growth and chemosensitivity. Taken together, the current study demonstrates a novel mechanism that regulates the Hippo pathway and reveals TRM21 as a critical factor that promotes growth and chemoresistance in human HCC.

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The oncogenic roles and clinical implications of YAP/TAZ in breast cancer

Cited by 18 publications

References 149 publications

Matrix viscoelasticity controls epithelial cell mechanobiology through dimensionality

Matrix viscoelasticity controls epithelial cell mechanobiology through dimensionality

Hippo effector, Yorkie, is a Tumor Suppressor in SelectDrosophilaSquamous Epithelia

TRIM21 is critical in regulating hepatocellular carcinoma growth and response to therapy by altering the MST1/YAP pathway

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